Gamma-glutamyl transferase 5 overexpression in cerebrovascular endothelial cells improves brain pathology,cognition,and behavior in APP/PS1 mice

In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.

Progress and challenges of cerebrovascular endothelial cells research promoted by single-cell transcriptome sequencing technology

Single-cell transcriptome sequencing has been a rapidly developing and powerful biological tool in recent years,and it plays a vital role in describing tissue development,cell heterogeneity,stress response,etc.Cerebrovascular disease is one of the leading causes affecting human health in the world.Thus,it is important to understand the characteristics of cerebrovascular structure,function,and environmental response.Notably,single-cell transcriptome sequencing provides deeper insights into cerebrovascular research in health and disease states.This article will briefly introduce the basic structure and function of cerebrovascular endothelial cells(ECs),summarize the current research and new findings on cerebrovascular ECs at the single-cell transcriptome level,and discuss the challenges in this field.

Role of vascular endothelial growth factor B in nonalcoholic fatty liver disease and its potential value

Nonalcoholic fatty liver disease(NAFLD)refers to fatty liver disease caused by liver injury factors other than alcohol.The disease is characterized by diffuse fat infiltration,including simple steatosis(no inflammatory fat deposition),nonalcoholic fatty hepatitis,liver fibrosis,and so on,which may cause liver cirrhosis,liver failure,and even liver cancer in the later stage of disease progression.At present,the pathogenesis of NAFLD is still being studied.The"two-hit"theory,represented by lipid metabolism disorder and inflammatory reactions,is gradually enriched by the"multiple-hit"theory,which includes multiple factors,such as insulin resistance and adipocyte dysfunction.In recent years,vascular endothelial growth factor B(VEGFB)has been reported to have the potential to regulate lipid metabolism and is expected to become a novel target for ameliorating metabolic diseases,such as obesity and type 2 diabetes.This review summarizes the regulatory role of VEGFB in the onset and development of NAFLD and illustrates its underlying molecular mechanism.In conclusion,the signaling pathway mediated by VEGFB in the liver may provide an innovative approach to the diagnosis and treatment of NAFLD.

Pathological process of liver sinusoidal endothelial cells in liver diseases

Cirrhosis develops from liver fibrosis and is the severe pathological stage of all chronic liver injury. Cirrhosis caused by hepatitis B virus and hepatitis C virus infection is especially common. Liver fibrosis and cirrhosis involve excess production of extracellular matrix,which is closely related to liver sinusoidal endothelial cells(LSECs). Damaged LSECs can synthesize transforming growth factor-beta and platelet-derived growth factor,which activate hepatic stellate cells and facilitate the synthesis of extracellular matrix. Herein,we highlight the angiogenic cytokines of LSECs related to liver fibrosis and cirrhosis at different stages and focus on the formation and development of liver fibrosis and cirrhosis. Inhibition of LSEC angiogenesis and antiangiogenic therapy are described in detail. Targeting LSECs has high therapeutic potential for liver diseases. Further understanding of the mechanism of action will provide stronger evidence for the development of anti-LSEC drugs and new directions for diagnosis and treatment of liver diseases.

Endothelial progenitor cells in cardiovascular diseases

Endothelial dysfunction has been associated with the development of atherosclerosis and cardiovascular diseases. Adult endothelial progenitor cells(EPCs) are derived from hematopoietic stem cells and are capable of forming new blood vessels through a process of vas-culogenesis. There are studies which report correlations between circulating EPCs and cardiovascular risk fac-tors. There are also studies on how pharmacotherapies may influence levels of circulating EPCs. In this review, we discuss the potential role of endothelial progenitor cells as both diagnostic and prognostic biomarkers. In addition, we look at the interaction between cardio-vascular pharmacotherapies and endothelial progenitor cells. We also discuss how EPCs can be used directly and indirectly as a therapeutic agent. Finally, we evalu-ate the challenges facing EPC research and how these may be overcome.

Traditional and Non-Traditional Risk Factors Involved with Endothelial Dysfunction and Arterial Stiffness in Autoimmune Rheumatic Diseases

Autoimmune rheumatic diseases (ARDs) have been closely associated with accelerated plaque progression and the development of atherosclerosis, which lead to high morbidity and mortality rates for cardiovascular diseases. Endothelial dysfunction and arterial stiffness are greatly evidenced in several studies in the early phase of atherosclerosis. In ARDs, endothelial dysfunction and arterial stiffness are related to traditional and non-traditional risk factors. To date, no studies have clearly analyzed the main parameter involved in endothelial dysfunction and arterial stiffness. In this context, the present narrative review’s purpose was to describe the main factor in endothelial dysfunction and arterial stiffness in different ARDs. Endothelial dysfunction and arterial stiffness are related to traditional risk factors (i.e., hypertension, diabetes, dyslipidemia, metabolic syndrome, sedentary behavior) and non-traditional risk factors (linked to the immune mechanisms involved in these diseases). Moreover, in the present study, these associations were systemically analyzed in ankylosing spondylitis, antiphospholipid syndrome, rheumatoid arthritis, psoriatic arthritis, systemic autoimmune myopathies, systemic lupus erythematosus and systemic sclerosis. The present review shows that the relationship of traditional risk factors and non-traditional risk factors related to ARDs works in the worsening of function and structural properties of arterial vessels, leading to high cardiovascular morbidity and mortality.

The role of prolactin/vasoinhibins in cardiovascular diseases

Prolactin(PRL)is a polypeptide hormone that is mainly synthesized and secreted by the lactotroph cells of the pituitary.There are two main isoforms of PRL:23-kDa PRL(named full-l ength PRL)and vasoinhibins(including 5.6–18 kDa fragments).Both act as circulating hormones and cytokines to stimulate or inhibit vascular formation at different stages and neovascularization,including endothelial cell proliferation and migration,protease production,and apoptosis.However,their effects on vascular function and cardiovascular diseases are different or even contrary.In addition to the structure,secretion regulation,and signal transduction of PRL/vasoinhibins,this review focuses on the pathological mechanism and clinical significance of PRL/vasoinhibins in cardiovascular diseases.

Relationship of Inflammation and Endothelial Dysfunction with Risks to Cardiovascular Disease among People in Inner Mongolia of China

Objective To explore the relationship of inflammation and endothelial dysfunction with risks to cardiovascular disease （CVD）. Methods Blood pressure, body weight, body height, waist circumference and lifestyle risk factors were measured and studied among 2589 participants in Inner Mongolia of China, and biomarkers of inflammation and endothelial dysfunction including high-sensitivity C-reactive protein （hsCRP）, soluble inter-cellular adhesion molecule-1 （slCAM-1）, soluble E-selectin （sE-selectin）, and angiotensin II were investigated. Results Subjects with metabolic risk factors for CVD had higher levels of hsCRP, sE-selectin and slCAM-1 than those without such risk factors （all P〈O.05）. Levels of all biomarkers positively and significantly increased with aggregation of the metabolic risk factors among the subjects （all P for trend 〈0.001）. Data from the multivariate analysis showed that participants with high levels of hsCRP [odds ratio （OR}： 1.96, 95% confidence interval （CI）： 1.52-2.53], sE-selectin （OR： 1.35, 95% Cl： 1.05-1.72）, and angiotensin II （OR： 1.81, 95% CI＂ 1.40-2.33） were more likely to develop hypertension; participants with high levels of hsCRP （OR： 2.33, 95% CI： 1.85-2.94）, sE-selectin （OR： 1.24, 95% CI： 1.00-1.54）, and slCAM-1 （OR： 1.70, 95% CI： 1.30-2.22） were more likely to develop dyslipidemia, and those with high levels of hsCRP （OR： 2.95, 95% CI： 2.27-3.83） and slCAM-I（OR： 2.80, 95% CI： 2.06-3.80） were more likely to develop hyperglycemia. Conclusion Biomarkers of inflammation and endothelial dysfunction were separately associated with relevant metabolic risk factors for CVD. And appropriate measures should be taken to control inflammation and improve endothelial function among individuals with different metabolic risk factors for CVD.

Endothelial dysfunction as a predictor of cardiovascular disease in type 1 diabetes

Macro and microvascular disease are the main cause of morbi-mortality in type 1 diabetes(T1DM).Although there is a clear association between endothelial dysfunction and atherosclerosis in type 2 diabetes,a cause-effect relationship is less clear in T1 DM.Although endothelial dysfunction(ED) precedes atherosclerosis,it is not clear weather,in recent onset T1 DM,it may progress to clinical macrovascular disease.Moreover,endothelial dysfunction may either be reversed spontaneously or in response to intensive glycemic control,long-term exercise training and use of statins.Acute,long-term and post-prandial hyperglycemia as well as duration of diabetes and microalbuminuria are all conditions associated with ED in T1 DM.The pathogenesis of endothelial dysfunction is closely related to oxidative-stress.NAD(P)H oxidase over activity induces excessive superoxide production inside the mitochondrial oxidative chain of endothelial cells,thus reducing nitric oxide bioavailability and resulting in peroxynitrite formation,a potent oxidant agent.Moreover,oxidative stress also uncouples endothelial nitric oxide synthase,which becomes dysfunctional,inducing formation of superoxide.Other important mechanisms are the activation of both the polyol and protein kinase C pathways as well as the presence of advanced glycation end-products.Future studies are needed to evaluate the potential clinical applicability of endothelial dysfunction as a marker for early vascular complications in T1 DM.

Relationship between testosterone and indexes indicating endothelial function in male coronary heart disease patients

Aim： To investigate the relationship between androgen level and the indexes indicating endothelial function in male patients with coronary heart disease （CHD）. Methods： We registered the following data for 106 50-70-year-old men： age, weight, blood lipid, including total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol and triglyceride, whether a smoker, sugar levels, blood pressure, free testosterone （FT）, vascular cell adhesion molecule- 1 （VCAM- 1） and the intima-media thickness （IMT） of common carotid artery, common carotid diameter, maximum velocity in systolic phase, minimum velocity in diastolic phase and resistent index. Among the 106 men, 51 were patients with CHD. The relationships between FT level, VCAM-1 concentration and IMT were examined, respectively, using a stepwise linear regression technique among all the 106 men. Results： There was no statistical difference in terms of age, blood pressure, whether a smoker, sugar levels, HDL-C, minimum velocity in diastolic phase, resistent index between male CHD patients and controls; whereas results for weight, total cholesterol, low density lipoprotein cholesterol, triglyceride, VCAM- 1 and IMT of male CHD patients were higher than those of controls; FT level and maximum velocity in systolic phase were lower. It was found that among all the objects, FT level was inversely correlated with IMT and VCAM-1 concentration. Condusion： FT level was inversely correlated with VCAM-I concentration and IMT which are indicators of endothelial function. （Asian JAndro12008 Mar; 10： 214-218）

Blood-brain barrier pathology in cerebral small vessel disease

Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly.Although at first it was considered innocuous,small vessel disease is nowadays regarded as one of the major vascular causes of dementia.Radiological signs of small vessel disease include small subcortical infarcts,white matter magnetic resonance imaging hyperintensities,lacunes,enlarged perivascular spaces,cerebral microbleeds,and brain atrophy;however,great heterogeneity in clinical symptoms is observed in small vessel disease patients.The pathophysiology of these lesions has been linked to multiple processes,such as hypoperfusion,defective cerebrovascular reactivity,and blood-brain barrier dysfunction.Notably,studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel disease.Therefore,the purpose of this review is to provide a new foundation in the study of small vessel disease pathology.First,we discuss the main structural domains and functions of the blood-brain barrier.Secondly,we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel disease.Finally,we conclude with a discussion on future perspectives and propose potential treatment targets and interventions.

Excess cardiovascular mortality in men with non-alcoholic fatty liver disease:A cause for concern!

Non-alcoholic fatty liver disease(NAFLD)has emerged as the commonest cause of chronic liver disease worldwide in recent years.With time,our understanding of NAFLD has evolved from an isolated liver condition to a systemic disease with significant manifestations beyond the liver.Amongst them,cardiovascular diseases(CVDs)are the most important and clinically relevant.Recent research supports a strong independent link between NALFD and CVD beyond the shared risk factors and pathophysiology.Female sex hormones are well known to not only protect against CVD in pre-menopausal females,but also contribute to improved adipose tissue function and preventing its systemic deposition.Recent research highlights the increased risk of major adverse cardiovascular-cerebral events(MACCE)amongst male with NAFLD compared to females.Further,racial variation was observed in MACCE outcomes in NAFLD,with excess mortality in the Native Americans and Asian Pacific Islanders compared to the other races.

Intrahepatic vascular changes in non-alcoholic fatty liver disease: potential role of insulin-resistance and endothelial dysfunction

Metabolic syndrome is a cluster of several clinical conditions characterized by insulin-resistance and high cardiovascular risk. Non-alcoholic fatty liver disease is the liver expression of the metabolic syndrome, and insulin resistance can be a frequent comorbidity in several chronic liver diseases, in particular hepatitis C virus infection and/or cirrhosis. Several studies have demonstrated that insulin action is not only relevant for glucose control, but also for vascular homeostasis. Insulin regulates nitric oxide production, which mediates to a large degree the vasodilating, antiinflammatory and antithrombotic properties of a healthy endothelium, guaranteeing organ perfusion. The effects of insulin on the liver microvasculature and the effects of IR on sinusoidal endothelial cells have been studied in animal models of non-alcoholic fatty liver disease. The hypotheses derived from these studies and the potential translation of these results into humans are critically discussed in this review.

The relationship between amyloid-beta and brain capillary endothelial cells in Alzheimer's disease

Neurovascular dysfunction,as an integral part of Alzheimer's disease,may have an important influence on the onset and progression of chronic neurodegenerative processes.The bloodbrain barrier(BBB)pathway is one of the main pathways that mediates the clearance of amyloidbeta(Aβ)in the brain parenchyma.A large number of studies have shown that receptors and ATPbinding cassette transporte rs expressed on endothelial cells play an important role in Aβtransport across the BBB,but the specific mechanism is not clear.In this review,we summarize the possible mechanisms of Aβproduction and clearance,and in particular the relationship between Aβand brain capillary endothelial cells.Aβis produced by abnormal cleavage of the amyloid precursor protein via amyloidogenic processing under pathological conditions.Dys regulation of Aβclearance is considered to be the main reason for the massive accumulation of Aβin the brain parenchyma.Several pathways mediating Aβclearance from the brain into the periphery have been identified,including the BBB pathway,the blood-cerebros pinal fluid barrier and arachnoid granule pathway,and the lymphoidrelated pathway.Brain ca pilla ry endothelial cells are the key components of Aβclearance mediated by BBB.Receptors(such as LRP1,RAGE,and FcRn)and ATP-binding cassette transporters(such as P-gp,ABCA1,and ABCC1)expressed on endothelial cells play a critical role in Aβtranscytosis across the BBB.The toxic effects of Aβcan induce dysregulation of receptor and transpo rter expression on endothelial cells.Excessive Aβexerts potent detrimental cerebrovascular effects by promoting oxidative stress,inducing chronic inflammation,and impairing endothelial structure and functions.All of these are main causes for the reduction in Aβclearance across the BBB and the accumulation of Aβin the brain parenchyma.Therefo re,studies on the intera ctions between Aβand brain capillary endothelial cells,including their receptors and transporters,studies on inhibition of the toxic effects of Aβon endothelial cells,and studies on promoting the ability of endothelial cells to mediate Aβclearance may provide new therapeutic strategies for Aβclearance in Alzheimer's disease.

Cognitive impairment in cerebral small vessel disease induced by hypertension

Hypertension is a primary risk factor for the progression of cognitive impairment caused by cerebral small vessel disease,the most common cerebrovascular disease.Howeve r,the causal relationship between hypertension and cerebral small vessel disease remains unclear.Hypertension has substantial negative impacts on brain health and is recognized as a risk factor for cerebrovascular disease.Chronic hypertension and lifestyle factors are associated with risks for stro ke and dementia,and cerebral small vessel disease can cause dementia and stroke.Hypertension is the main driver of cerebral small vessel disease,which changes the structure and function of cerebral vessels via various mechanisms and leads to lacunar infarction,leukoaraiosis,white matter lesions,and intracerebral hemorrhage,ultimately res ulting in cognitive decline and demonstrating that the brain is the to rget organ of hypertension.This review updates our understanding of the pathogenesis of hypertensioninduced cerebral small vessel disease and the res ulting changes in brain structure and function and declines in cognitive ability.We also discuss drugs to treat cerebral small vessel disease and cognitive impairment.

Androgen actions on endothelium functions and cardiovascular diseases

The roles of androgens on cardiovascular physiology and pathophysiology are controversial as both beneficial and detrimental effects have been reported. Although the reasons for this discrepancy are unclear, multiple factors such as genetic and epigenetic variation, sex-specificity, hormone interactions, drug preparation and route of administration may contribute. Recently, growing evidence suggests that androgens exhibit beneficial effects on cardiovascular function though the mechanism remains to be elucidated. Endothelial cells （ECs） which line the interior surface of blood vessels are distributed throughout the circulatory system, and play a crucial role in cardiovascular function. Endothelial progenitor cells （EPCs） are considered an indispensable element for the reconstitution and maintenance of an intact endothelial layer. Endothelial dysfunction is regarded as an initiating step in development of atherosclerosis and cardiovascular diseases. The modulation of endothelial functions by androgens through either genornic or nongenomic signal pathways is one possible mechanism by which androgens act on the cardiovascular system. Obtaining insight into the mechanisms by which androgens affect EC and EPC functions will allow us to determine whether androgens possess beneficial effects on the cardiovascular system. This in turn may be critical in the prevention and therapy of cardiovascular diseases. This article seeks to review recent progress in androgen regulation of endothelial function, the sex-specificity of androgen actions, and its clinical applications in the cardiovascular system.

Endothelial progenitor cells and coronary artery disease:Current concepts and future research directions

Vascular injury is a frequent pathology in coronary artery disease.To repair the vasculature,scientists have found that endothelial progenitor cells(EPCs)have excellent properties associated with angiogenesis.Over time,research on EPCs has made encouraging progress regardless of pathology or clinical technology.This review focuses on the origins and cell markers of EPCs,and the connection between EPCs and coronary artery disease.In addition,we summarized various studies of EPC-capturing stents and EPC infusion therapy,and aim to learn from past technology to predict the future.

Intrastriatal Gene Transfer of Vascular Endothelial Growth Factor Rescues Dopaminergic Neurons in a Rat Parkinson's Disease Model

To examine the ability of intrastriatal gene transfer of vascular endothelial growth factor 165 mediated by adenoviral vector to rescue dopaminergic neurons in a rat model of Parkinson＇s disease （PD）, we constructed recombinant replication-deficent adenoviral vectors carrying the gene of VEGF165 （Ad-VEGF）, and injected Ad-VEGF （or Ad-LacZ and PBS as controls） into the striatum of rats 7 days after the lesion by 6-hydroxydopamine. The rat rotational behavior analysis and tyrosine hydroxylase （TH） immunohistochemistry were performed to assess the change of dopaminergic neurons. Our results showed that the rats receiving Ad-VEGF injection displayed a significant improvement in apomorphine-induced rotational behavior and a significant preservation of TH-positive neurons and fibers compared with control animals, It is concluded that intrastriatal gene transfer by Ad-VEGF may rescue the dopaminergic neurons from degeneration in a rat model of PD.

Tongxinluo promotes endothelium-dependent arteriogenesis to attenuate diabetic peripheral arterial disease

BACKGROUND Peripheral arterial disease(PAD)has become one of the leading causes of disability and death in diabetic patients.Restoring blood supply to the hindlimbs,especially by promoting arteriogenesis,is currently the most effective strategy,in which endothelial cells play an important role.Tongxinluo(TXL)has been widely used for the treatment of cardio-cerebrovascular diseases and extended for diabetes-related vascular disease.AIM To investigate the effect of TXL on diabetic PAD and its underlying mechanisms.METHODS An animal model of diabetic PAD was established by ligating the femoral artery of db/db mice.Laser Doppler imaging and micro-computed tomography(micro-CT)were performed to assess the recovery of blood flow and arteriogenesis.Endothelial cell function related to arteriogenesis and cellular pyroptosis was assessed using histopathology,Western blot analysis,enzyme-linked immunosorbent assay and real-time polymerase chain reaction assays.In vitro,human vascular endothelial cells(HUVECs)and human vascular smooth muscle cells(VSMCs)were pretreated with TXL for 4 h,followed by incubation in high glucose and hypoxia conditions to induce cell injury.Then,indicators of HUVEC pyroptosis and function,HUVECVSMC interactions and the migration of VSMCs were measured.RESULTS Laser Doppler imaging and micro-CT showed that TXL restored blood flow to the hindlimbs and enhanced arteriogenesis.TXL also inhibited endothelial cell pyroptosis via the reactive oxygen species/nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3/Caspase-1/GSDMD signaling pathway.In addition,TXL restored endothelial cell functions,including maintaining the balance of vasodilation,acting as a barrier to reduce inflammation,and enhancing endothelial-smooth muscle cell interactions through the Jagged-1/Notch-1/ephrin-B2 signaling pathway.Similar results were observed in vitro.CONCLUSION TXL has a pro-arteriogenic effect in the treatment of diabetic PAD,and the mechanism may be related to the inhibition of endothelial cell pyroptosis,restoration of endothelial cell function and promotion of endothelial cell-smooth muscle cell interactions.

Single-Cell RNA Sequencing Reveals Potential for Endothelial-to-Mesenchymal Transition in Tetralogy of Fallot

Background:Tetralogy of Fallot(TOF)is a very common cyanotic congenital heart disease.Endothelial-to-mesenchymal transition(EndoMT)is recognized as a physiological mechanism involved in embryonic heart development and endothelial formation.However,there is still a gap in the reports related to the mechanism of EndoMT development in TOF.Methods:First,transcriptomic data of single cell nuclei of TOF and Donor were obtained based on the Gene Expression Omnibus(GEO)database,and the data were normalized and clus-tered by dimensionality reduction using the Seurat package.Subsequently,differentially expressed genes(DEGs)between TOF and Donor were screened using the“FindMarkers”function,and the gene sets of interest were enriched.Finally,to characterize the dynamics of EndoMT occurrence in TOF,we performed pseudotime cell tra-jectory inference as well as utilized SCENIC analysis to probe the gene regulatory networks(GRNs)dominated by transcription factors(TFs)in endothelial cells.Results:We identified a total of six cell clusters based on single-cell nuclear transcriptome data from TOF and Donor.We found that 611 genes with up-regulated expression within TOF showed conversion to mesenchyme.By subdividing endothelial cell subtypes,endothelial cells 2 were shown to be involved in cell adhesion,migration and extracellular matrix processes.Pseudo-time and SCENIC analyses showed that endothelial cell 2 has EndoMT potential.In addition,ERG and TEAD1 are TFs that play key reg-ulatory roles in this subtype,and both of their target genes are also highly expressed in TOF.This demonstrates that ERG and TEAD1 effectively promote the EndoMT process.Conclusion:Our study reveals the molecular mechanisms underlying the development of EndoMT in TOF,which demonstrates that manipulating the endothelial-to-mesenchymal transition may offer unprecedented therapeutic potential for the treatment of TOF.